TWI333487B - Substituted 2 -thio -3, 5 - dicyano -4- phenyl -6- aminopyrid ines and their use - Google Patents

Description

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10 15 The present invention relates to substituted 2, Fushun spray 'About JL theory + 3,5-monocyano-4-phenyl-6-amino group_pure method and _ adenine nucleoside'- a kind of nucleus containing endogenous ribose, which has a fine secretive activity, and is - Μ*5 sub-specially for the treatment of cells with damaged oxygen and limited supply of cells Brain) in the case of ischemia. : Xizhiyiguan (for example, heart = partial to adenine nucleus Pu-5, Shanqing Μ ρ) and s - gland for potting during the period of intracellular - intermediate production, = can be released from this In the case, it acts by a hormone-like substance or neurotransmitter by binding to the symbe of the trait. The second: the free adenine nucleoside in the extracellular region under the f pressure condition is very low. However, under hypoxic or hypoxic conditions, the extracellular rolling of the 'glandular nucleosides' in the affected prosperous has increased dramatically. Thus, for example, glandular nucleosides inhibit agglomeration of the gold platelets and increase blood supply to the coronary arteries. Furthermore, it can be at the heart rate, the release of neurotransmitters and the specialization of lymphocytes. -λ- Ganzi

The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative printed - gland, purine nucleosides, these actions are aimed at increasing the oxygen supply of the affected device S and / (iv) lowering the metabolism of these organs to adjust the organ to hypoxia or low The metabolism of the elder's supply of oxygen under oxygen conditions. 20 The action of purine nucleosides is mediated through specific receptors. To date, A2a 'A2b and A3 subtypes have been known. The actions of these adenosine nucleoside receptors are transmitted intracellularly by messenger cAMP. In the case where the glandular nucleus binds to the A2a or A2b receptor, the intracellular cAMp is increased by activation of the membrane-bound adenylate cyclase, and when adenine is activated

91500A 1333487 A7 V. INSTRUCTIONS (2) When nucleosides bind to Al < A3 receptors, the intracellular cAMP rolling is reduced by the inhibition of glandular acid cyclase. According to the invention, adenine nucleoside-receptor-selective ligand is a sub-cracking substance f that selectively binds to one or more adenine nuclear receptors, The action of purine nucleoside (adenine nucleoside agonist) or its action (adenine nucleoside antagonist). In the specification of the present invention, adenine nucleoside receptor ligand, if, first, is clear One or more adenine nucleoside receptor subtypes are active and, secondly, one or more other adenine nucleoside receptor subtypes have a relatively low activity (factor 1 〇 or lower) , means ', selected', where, if there is, there is a test method for the selectivity of the action, refer to the test method described in the section All. According to their receptor selectivity, adenosine-receptor-selective ligands can be classified into different classes, for example, a ligand that selectively binds to the A1 15 or A2 receptor of adenine, and The latter case is also, for example, those that selectively bind to A2a or A2b receptors of adenine. Adenine nucleoside receptor ligands that selectively bind to adenine nucleoside receptor subtypes, for example, ligands that selectively bind to adenine nucleosides Α1 and Α2, but do not bind to A3 receptors can. 20 The above receptor selectivity can be determined by the effect of the substance on the cell line, which exhibits the receptor subtype mentioned after stable transfection with the relevant cDNA (see Biochemistry 267 (1992) No. 10764 -1〇770 pages of publications, ME·Oulan, H. Rui, J. Ouchuschiski, KA·Jia Kesen, GL Sidney's unique clone of bovine A1 adenine nucleoside receptor, table- 4- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)' — 1 word of the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1333487 A7 B7 V. Invention description (3) Present, and characteristics The study of site-directed mutagenesis at the site of ligand binding"" is fully incorporated herein by reference. The effect of this substance on these cell lines can be determined by biochemical measurements of intracellular messenger cAMP. Monitoring (see KN寇z, j. Hailin, J. 5 Sigger' C. Auman, B. Chur, BB Philippine, MJ Ross,,, Comparative Pharmacology of Human Adenine Nucleoside Receptor Subtypes - Characteristics of stable transfected receptors in CHO cells', published in Naunyn Schmiedebergs Arch. Pharmacol. 357 (1998), pp. 1-9, the disclosure of which is hereby incorporated by reference in its entirety in its entirety in the the the the the the the the the the the the the Decreased cAMP concentration (should be directly after pre-stimulation of adenylate cyclase by forskolin), in the case of A1 antagonists, 'increased intracellular cAMP concentration is observed (suitable for adenine nucleus) After pre-stimulation of arbuscular or adenine-like nucleosides plus direct pre-stimulation of glandular acid cyclase by Fukolin 15,), A2a and A2b agonists (preferably via Gs protein coupling) cause CAMP in cells. The concentration is increased and the A2a and A2b antagonists are reduced. In the case of the A2 receptor, it is not helpful to pre-stimulate adenylate cyclase directly by Fukon. The "adenosine-receptor-specific" ligand known in the art is a major derivative of the adenosine nucleoside according to the day (S.-A. Posen and RJ Kunn, adenine nucleoside) Receptors: a new opportunity for future drugs, Machines and Medicinal Chemistry 6 (1998) pp. 619-641). However, most of the known adenine nucleoside ligands have the disadvantage that their effects are not completely specific receptors, and their activity is more natural than adenosine nucleosides. Low or it is only available on the paper scale after oral administration. Chinese National Standard (CNS) A4 specification (210 X 297 public) 1333487 B7 A7

The substituted thiazolyl group or any phenyl group substituted by a halogen, (Ci_C4).alkyl or (C1-C4)-homooxy group up to three times. Depending on the type of substitution, the compounds of formula (I) may exist in stereoisomeric forms in that they are mutually imaged and mirror imaged (mirroromers) or not imaged and mirrored (non-5 enantiomers). The present invention is directed to both mirror image or diastereoisomers and mixtures thereof. The racemate form can be separated into a homogeneous set of components in a known manner, as in the case of diastereoisomers. Likewise, the invention also relates to other tautomers of the compounds of formula (1) and salts thereof. The salt of the compound of the formula (1) may be a physiologically acceptable salt of a compound according to the present invention and an inorganic acid, a slow acid or a sulfonic acid. Particularly preferred is with hydrogen acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, trifluoroacetic acid, acetic acid, propionic acid, lactic acid, tartaric acid. a salt of citric acid, trans-maleic acid, maleic acid or stupid 15 formic acid. Salts that may be mentioned in the printing of the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs include salts with conventional bases, such as metal salts (eg, sodium salts or salt removal), such as soil test metal salts (eg , the word salt or magnesium salt) or from ammonia or organic amines, such as 'diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-mercapto oxime , 2 20 Hydrogen rosin (dihydrobietylamine) 1- 1-ephenamine ephenamine or methyl hexahydropyridine, derived from the salt. According to the present invention, the compound of the formula (I) which can be in a solid or liquid state by hydration with water or covalently with a solvent molecule to form a molecular compound or complex is referred to as a hydrate or a solvate, respectively. Examples of hydrates are paper grades applicable to the National Standard for National Standards (CNS) A4 (210 X 297 mm) 1333487 Α7 Β7 V. Description of invention (6) sesquihydrate, monohydrate, dihydrate or trihydrate Similarly to the substance β, a hydrate or a solvate of a salt of the compound according to the present invention is also suitable. Furthermore, the invention also includes prodrugs of the compounds according to the invention. According to the present invention, those of the formula (I) which are themselves biologically active or inactive but which can be converted into a relevant biologically active form under physiological conditions (e.g., metabolically or solvently) are referred to as prodrugs. Unless otherwise stated, in the specification of the present invention, the substituent has the following definition: Halogen generally represents fluorine, chlorine, bromine or iodine. Fluorine, gas or bromine is preferred. It is best to use 10 fluorine or chlorine. The (CVC4)-alkyl group generally represents an alkyl group having a straight chain or a branch having 1 to 4 carbon atoms. Mention may be made, by way of example, of mercapto, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl and tert-butyl. The (CrC4)-alkoxy group represents a 15 alkoxy group having 1 to 4 carbon atoms in a straight chain or a branch. Mention may be made, by way of example, of decyloxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, second butoxy, isobutoxy and tert-butoxy. The Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printed the preferred compound of formula (I), its salts, hydrates, salts hydrates and solvates 20 where η represents the number 2, R1 represents hydrogen, fluorenyl Or ethyl, and R2 represents a pyridyl or thiazolyl group, the moiety of which may be substituted by the following: fluorenyl*ethyl*gas*chloro*amine-dimethylamino*ethanoamine National Standard (CNS) A4 Specification (210 X 297 mm) 1333487 A7 B7 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 5, Invention Description (Base, Mercapto, 2-Pyridylamino, 4-Pyridylamino) , thiophenyl, ° pyridine, morpholinyl, hexahydropyridyl, any thiazolyl group substituted by fluorenyl or any phenyl substituted by gas or methoxy group up to three times. A compound of the formula (1), wherein R1 is hydrogen or methyl. Particularly preferred are also compounds of the formula (I), and salts, hydrates, hydrates and solvates thereof, wherein 'n represents a number 2, 10 Rl represents hydrogen or a fluorenyl group, and R2 represents a pyridyl group or a thiazolyl group, a part thereof may be Substituted by the column: methyl 'gas, amine, dimethylamino, ethyl hydrazino, fluorenyl, 2-pyridylamino, 4-pyridylamino, thienyl, pyridyl, rifampin a group, a 2-methylthiazole-5-yl group, a phenyl group, a 4, gas phenyl group or a 3,4,5-tri 15 decyloxyphenyl group. Particularly preferred is a compound having the following structural formula from Example 6 And its salts, hydrates, hydrates and solvates of salts.

^OH

S -9- This paper scale applies to China National Standard (CNS) A4 specification (2丨0x297 mm) 1333487 A7 B7 V. Inventive Note (8) The present invention also provides a method for preparing a compound of formula (I), which is characterized in that Compound of formula (II) 10 0-R , i: CH 2 ) n

(II), 15 wherein η and R1 are as defined above, reacting with a compound of formula (III) r2-ch2-x (III)

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperative, R2 is defined as before, and X represents a suitable release group, for example and preferably 20 halogen, especially gas, bromine or iodine, or methane sulfonate, Toluenesulfonate, trifluorosulfonate or imidazolyl, if appropriate, is carried out in the presence of a base. The above method can be illustrated by the following equation flow chart: -10- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1333487 A7 B7 V. Description of invention (9)

Η,Ν N SH (Π) -

Br-

,R

10 15 20 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printing 25 In the process of the present invention, suitable solvents are all organic solvents which are inert under the reaction conditions. These include alcohols such as sterols, ethanol and isopropanol, ketones such as acetone and mercaptoethyl ketone, acyclic and cyclic ethers, for example, diethyl hydrazine and tetrahydrofuran, vinegar Classes, for example, ethyl acetate or butyl acetate, hydrocarbons, for example, benzene, diphenyl, benzene, hexane or cyclohexane, gasified hydrocarbons, for example, di-methane, di-benzene or dichloride Ethane, or other solvent, for example, dimethylformamide, sulfoxide (DMSO). Water is also a suitable solvent amine. Mixtures of the above solvents can also be used. Suitable bases are conventional inorganic or organic base hydroxides such as sodium hydroxide or hydroxide, or metal carbonates such as sodium or potassium carbonate, or alkali metal hydrogencarbonates, for example , sodium bicarbonate or potassium bicarbonate, or metal oxide oxide, for example, sodium or potassium methoxide, sodium or potassium ethoxide or potassium butoxide, or guanamines, for example, sodium amide, double (three Methyl nonyl) lithium amide or lithium diisopropyl guanamine, or an organometallic compound such as butyl lithium or phenyl lithium, or 1,8-diazabicyclo[5,4,0] 1--7-ene (DBU) or 1,5-diazabicyclo-11-acetonitrile, pyridine or bis-quinone hydrazine. These should include gold. This paper scale applies to China National Standard (CNS) A4 specifications. (210x297 mm) -- - IJ33487 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Description of Invention (10) [4.3.0]壬-5-ene (DBN), or other amines, for example, _ Bisamine and >» than bite. It is preferably a bismuth metal carbonate and an alkali metal hydrogencarbonate. Here, the base is used in an amount of from 10 to 10 moles, based on 1 mole of the compound (,), preferably: To 5 m, especially for 4 5 ears. The reaction is usually carried out at a temperature ranging from -78t to +H〇t: preferably between -78 ° C and +40 ° C, particularly at room temperature. The reaction can be carried out under atmospheric pressure, rising or decreasing pressure (e.g., from 0.5 to 5 bar). Usually, the reaction is carried out in 10 rows at atmospheric pressure. The compound of the formula (Π) itself is known to those skilled in the art or can be prepared by conventional methods known in the literature, for example, by reacting a related benzofural with cyanothioketamine. And prepared. In particular, reference is made to the following publications. [Obviously, their respective contents are incorporated herein by reference: • Dachik et al., Russian Chemical Journal, Vol. 33, No. 7, 1997, 1014 to 1017 Pages and 34, No. 4, 1998, pp. 557-563; • Dachik et al., Heterocyclic Compound Chemistry, Vol. 34, No. 2, 2〇 1998, pp. 188-194; • Kundi La et al., European Journal of Medicinal Chemistry, Vol. 33, 1998, pp. 887-897; • Candil et al., Zeitschift ftir Naturforschung 42b, 107 to 111 (1987). -12- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)

1333487 A7 B7 V. DESCRIPTION OF THE INVENTION (Π) Thus, for example, a compound of the formula (II) can also be produced by reacting a compound of the formula (IV) with an alkali metal sulfide. This method of preparation can be illustrated by the following equation flow chart for illustrating: 10

+ Na^S, Na

(II) The base sulfide used is preferably from 1 to 10 moles of sodium sulfide, preferably from 1 to 5 moles, particularly from 1 to 1 mole of the compound of the formula (IV). 4 Moer. 15 Suitable solvents are all organic solvents which are inert under the reaction conditions. These include, for example, N,N-dimercaptocarbamide, N-decylpyrrolidone, pyridine and acetonitrile. Preferably, N,N-dimercaptocarboxamide. Mixtures of the above solvents may also be used. The reaction is usually in the range of from +20 ° C to + 140 ° C, preferably 20 in the range from +20 ° C to +120 ° C, especially from +60 ° C to +l 〇〇 Between °C. The reaction can be carried out under atmospheric pressure, rising or decreasing pressure (e.g., from 0.5 to 5 bar). Usually, the reaction is carried out under atmospheric pressure. 0 -13- This paper scale applies to the Chinese national standard (CNS> A4 specification (210 X 297 mm). The Ministry of Economic Affairs, the Intellectual Property Bureau, the employee consumption cooperative, the printer's formula (1) It is particularly suitable, for example, to reduce the size of the area affected by myocardial infarction. Further, the compound of formula (1) is particularly suitable for, for example, prevention and/or treatment of thrombotic embolism diseases and ischemia, for example, myocardial infarction, stroke and transient 5 Ischemic seizures. Other particularly useful ranges for compounds of formula (1) are, for example, prevention and/or treatment of diseases of the genitourinary area, such as irritating bladder, erectile dysfunction and sexual dysfunction in women, and prevention and/or prevention and/or Treatment of inflammatory diseases such as 'asthmatic and inflammatory skin diseases, neurogenic 10 inflammatory diseases of the mesenteric nervous system' such as 'post-cerebral infarction status, Alzheimer's disease syndrome, and neurodegenerative diseases such as pain, And cancer. Particular mention is made, for example, in the prevention and/or treatment of respiratory diseases 'for example, asthma' chronic bronchitis Emphysema, bronchiectasis, mucoviscidosis, and pulmonary hypertension. 15 The compound of formula (1) is particularly suitable for, for example, prevention and/or treatment of polyuria, particularly diabetes. (I) Use of a compound for the preparation of a medicament for preventing and/or treating the above clinical phenomenon. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, the present invention relates to the prevention and/or treatment of a compound of the formula (1). 20 Method for describing a clinical phenomenon>> The object of the invention includes a pharmaceutical product comprising at least one compound of the formula (I), preferably containing one or more pharmaceutically acceptable adjuvants or carriers' and including it in the above-mentioned purposes For the appropriate administration, the compound of formula (I) can be used for all conventional dosage forms -15- This paper scale is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 7 48 5 5 ο 1Α Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed 20 invention description (! 4), that is, oral, non-gastrointestinal, inhalation, nasal, sublingual transrectal, local, for example, in the plant In the case of a product or a drainage strip, or for external use, for example, subcutaneously, in the case of parenteral administration, it may be specifically mentioned by intravenous, intramuscular and subcutaneous administration, for example, subcutaneously long. The agent is preferably administered orally or parenterally, especially for oral administration. - Here, the active compound can be administered by itself or in the form of a preparation. In particular, tablets, capsules, pills, dragees, tablets, granules, solid and liquid aerosols, syrup emulsions, suspensions and solutions. Here, the active compound must be present in such amounts to obtain a therapeutic effect. <<&gt; In general, the active compound may be present in a concentration of from 2 to 100% by weight, particularly from a concentration of from 5 to 9% by weight, preferably from 5 to 80% by weight. In particular, the concentration of the active compound should be from 0.5 to 9% by weight, i.e., the active compound should be present in an amount sufficient to achieve the dosage range recited. For this purpose, the active compounds can be converted into conventional preparations in a manner known per se. This can be accomplished by inert, non-toxic, pharmaceutically acceptable carriers, adjuvants, solvents, carriers, emulsifiers and/or dispersing agents. Auxiliaries which may be mentioned are, for example, water, non-toxic organic solvents, for example, paraffin, vegetable oils (for example, cedar oil), alcohols (for example, ethanol, propylene glycol), ethylene glycol (for example, polyethylene B). a diol), a solid carrier, for example, a natural or synthetic ground mineral (for example, talc or citrate), a saccharide (eg, 'lactose') emulsifier, a dispersant (eg, a polyethylene stalk), and A slip agent (for example, a town of sulfuric acid). In the case of oral administration, of course, the tablet contains additives. -16- This paper scale applies to China National Standard (CNS) A4 ϋΤ210χ297 mm) 1333487 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print V. Description of Invention (15) For example, sodium citrate, and adjuvants such as starch, gelatin and the like. The aqueous preparation for administration can be further blended with a flavor enhancer or dye. ~D In general, in the case of parenteral administration, administration at a dose of about 10,000 μg/kg body weight of 〇J is proven to be effective, from about to about 1000 micrograms/kg, especially By about 1 μg / kg 5 &amp; King about 1 〇〇 microgram / kg to achieve effective results. In the case of oral administration, the amount is from about 0.05 to about 5 mg/kg, preferably from about 1 to about 5 g/kg body weight, particularly from about 0.1 to about 1 mg/kg body weight. In addition to this, depending on the doses mentioned, depending on the body weight, the individual route of administration of the active compound, the type of formulation, and the time or interval at which administration occurs. The invention is illustrated by the following non-limiting examples, which are not intended to limit the invention. Unless otherwise stated, the percentages in the following examples are by weight in each case; parts are parts by weight. Α. Assessment of physiological activity I. Detection of cardiac jk tube effect After the chest is opened, the heart is quickly removed from the anesthetized mouse body and placed in a conventional Langedov device. The coronary arteries were perfused in a fixed volume (10 ml/min) and the resulting perfusion pressure was recorded using a suitable pressure sensor. In this assembly, the decrease in perfusion pressure refers to the relaxation associated with the coronary arteries. At the same time, the pressure generated by the heart during each contraction is determined by a balloon placed in the left ventricle and a second pressure sensor. The frequency at which the heart is separated in the pulsating heart is used in each time unit 5 1 10 15 20 -17- This paper size is applicable to China National Standard (CNS) A4 specification (2丨297 mm). Loading line 1333487 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 B7 V. Invention description (16) The number of shrinks is calculated. In this static assembly, the following values are the resulting reduction in heart rate (the percentage of δ main sense refers to the percentage reduction in heart rate at the concentrations mentioned): Example compound heart rate is reduced by one hundred fch at 1〇~ g/ml at 10^g/ml1 15.0% 17.5% 6 15.5% 20.0% II. Adenine nucleoside A1 'A2a, A2b and A3 agonistic detection a) Indirect detection of adenine nucleoside agonism by gene expression The cells of the CHO (Chinese voles ovary) permanent cell line were stably transfected with cDNA 10 encoding the adenosine nucleoside receptor subtypes Al, A2a and A2b. The adenosine nucleoside A1 is coupled to the adenylate cyclase by the Gi protein, and the adenine nucleoside A2a and A2b receptors are coupled by the Gs protein. Equivalent to this, the production of cAMP in the cells is inhibited or stimulated, respectively. Thereafter, the expression of the luminescent enzyme is regulated by a cAMP-dependent promoter. 15 The luminescent enzyme test, in order to achieve high sensitivity and regenerability, low variability and good adaptability when implanting a mechanical system, by changing multiple test parameters, such as cell density, growth phase and test incubation During the period, the concentration of Fouike and the composition of the medium were optimal. The following test protocols are used to illustrate the pharmacological properties of the cells and are used for mechanically assisted material testing screens. (: 5% C02, grown in DMEM/F12 medium containing 10% FCS (bovine fetal serum) and applied Chinese National Standard (CNS) A4 specification on every -18-sheet scale after 2-3 days (210x297 mm)

1333487 A7 B7 V. INSTRUCTIONS (17) In one case, it is divided into 1:10. The test cultures were seeded on a 384-well plate at a ratio of 1000 to 3000 cells per well and at 37. The cockroach grows for about 48 hours. The medium was then replaced with a physiological sodium carbonate solution (i3 mM sodium sulphate, 5 mM potassium carbonate, 2 mM calcium chloride, 20 mM HEPES, 1 mM gas 5H20, 5 mM NaHC03, pH 7.4). The substance dissolved in DMSO was diluted three times with 1:1 of this physiological sodium chloride solution and titrated into the assay culture (maximum final concentration of DMSO in the test mixture: _ 0.5%). In this manner, for example, from 5 μΜ to 5ηΜ of the final concentration of the sputum for 1 minute, the fucuron is added to the Α1 cell 10 and all the cultures are then incubated at 37 ° C for 4 hours. Thereafter, 35 μί contains 50% lysing reagent (30 mM disodium hydrogen phosphate, 10% glycerol '3% Triton XIOO, 25 mM TrisHCl, 2 mM dithiothreitol (DTT), pH 7.8) and 50% luminescent enzyme matrix Solution (2.5 mM ATP, 0.5 mM luciferin, O. ImM CoA, 10 mM Trioxin 15 (Zhuang 丨 (; 丨 1 ^) '1.351111 ^ magnesium sulfate, 151111 ^ 01 '1 ', ? 1 '17.8) solution The Ministry of Economic Affairs, the Intellectual Property Office, and the Consumer Cooperatives printed on the test culture, oscillated the plate for about 1 minute and measured the luciferase activity with a camera system to bind to all adenines with high affinity and an agitation effect. Nucleoside receptor subtypes were used as reference compounds in these experiments (寇z, KN 'Hailin, J_, Siegel, J., Auman, C., Kuril, B., Philippine, BB, Rose , MJ, Comparative Comparison of Human Adenosine Receptor Subtypes Pharmacology - Characteristics of Stable Transfected Receptors in CHO Cells" 'Naunyn Schmiedebergs Arch. Pharmacol. 357 (1998), pp. 1-9 ^ Table 1 below The values given in the examples are in different concentrations of Examples 1 and 6 - 19 - This paper scale applies to China Standard (CNS) A4 specification (210x297 mm) 1333487 A7 V. Description of invention (18) Compound stimulation (4) Gland (four) material receptor: under-type gain. Stimulation of the compound for glandular subtypes 4% 2% 8% Example 1 Example 6 A 0.3 nanometer ear 10 nanomoles 1 nanometer ear 0.3 奄 after ear 11% 56% 7% 25% ~45 %^~ 2% -1% 2% 4% ________ 0% 6% ~2%~ A29%~~-3% ~ ------ 0% Receptor subtype A1 A2a A2b Upper surface provides correlation The % value of the reference stimulus. The measured value of the necessary A2b receptor is the maximum value of the stimulus value achieved by NECA; the measurement value for the A1 receptor is based on the direct use of the micro molybdenum direct pre-stimulation material. The percentage value of the acid cyclase (related to the % value). 10 Thus, the A1 agonist has the effect of reducing the activity of the luminescent enzyme (measured value is less than 100%). b) The direct detection of adenosine nucleoside by testing cAMP The Department of Entrepreneurial Economics Intellectual Property Bureau employees collaborate with Du Yin to produce a stable transfection of cDNA encoding adenine nucleoside receptor subtypes Al, A2a, A2b and A3 (Chinese voles ovary) Fine cell line of 15 cells. Substance for binding based A2a or A2b receptor sub-type of by using a conventional use of a radioimmunoassay (cAMP RIA 'IBL GmbH, Germany, Hamburg) measuring cAMP levels within these cells, the cells). When a substance is used as an agonist, the binding of the substance is manifested by an increase in intracellular cAMP content. The combination is compatible with all of the high-affinity but -20- paper scales applicable to the Chinese National Standard (CNS) A4 specification (21〇X 297 mm) 1333487 A7 B7 5. Inventive Note (19) Not selective and The agonistic effect of the adenine nucleoside compound NECA (5-N-ethylcarboxylamido-adenine nucleoside) was used as a reference compound in these experiments (寇兹,Κ·N., 海林,J ., Sigg, J., Auman' C., Chur, B., Philippine, Β·Β., Ross, MJ, Human Adenine 5 Comparison of nucleoside receptor subtypes Pharmacology - CHO Characteristics of stable transfected receptors in cells", Naunyn Schmiedebergs Arch Pharmacol. 357 (1998), pp. 1-9). Adenine nuclear receptors A1 and A3 are coupled to the Gi protein, ie, stimulating these Inhibition of adenylate cyclase and subsequent reduction of 10 intracellular cAMP concentration "In order to confirm A1/A3 receptor agonist, adenylate cyclase is stimulated with focaine" However, additional stimulation of A1/A3 receptor This inhibits adenylate cyclase, which means that the A1/A3 receptor agonist can be detected in cells by relatively low levels of cAMP. Printed by the Ministry of Intellectual Property of the Ministry of Intellectual Property, in order to detect the antagonistic effect of adenine nucleoside receptors, recombinant cells transfected with the relevant 15 receptors are pre-stimulated with NECA and studied for pre-stimulation The resulting effect of a decrease in intracellular cAMP content. This binding to all XACs with high affinity and antagonistic effects is used as a reference compound in these experiments (Mu Le, CE 'History Tan, B. 'Adenine nucleoside receptor antagonists: structural and possibly 2 〇 therapeutic applications, Modern Pharmaceutical Design, 2 (1996) 501-530). 药物. Pharmacokinetics Research Pharmacokinetics Data A variety of substances are administered intravenously or orally to mice, rats and dogs. For this purpose, blood samples are collected for up to 24 hours after administration. The concentration of unaltered substances is measured by Bio-21- Applicable to China National Standard (CNS) A4 Specification (210 x 297 mm) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1333487 A7 B7 V. Description of Invention (20) Analytical Method (HPLC or HPLC-MS) The pharmacokinetic parameters were then investigated by the plasma concentration time course obtained in this way. The bioavailability of the different species is given in Table 2. Table 2: Bioavailable mouse large mouse after oral administration Example 22 of dog WO 00/125210 could not be measured* (administered orally at 3 mg/kg) Not available* (administered orally at 10 mg/kg) 1.47% (administered orally at 1 mg/kg) 1 compound 31.5% (administered orally at 1 mg/kg) 5.0% (administered orally at 3 mg/kg) 32.6% (administered orally at 3 mg/kg) 41.3% of the compound of Example 6 Oral administration of 3 mg/kg) 42.3% (administered orally at 3 mg/kg) 28.5% (administered orally at 1 mg/kg) * Plasma concentration at all measurement time points is below the measurement limit (&lt ; 1 μg / liter) B. Example: DBU 1,8-diazabicyclo[5.4.0]undec-7-ene 10 DMF Dimercaptodecylamine ESI Electrospray Dissociation (on MS) HEPES 2-[4-(2-hydroxyethyl)hexahydropyrazine and ethanesulfonic acid HPLC high pressure, high performance liquid chromatography bp boiling point 15 MS mass spectrometry -22- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)

1333487 A7 B7 V. INSTRUCTIONS (2) NMR pa RT Tris Preparation Example 1 Nuclear Magnetic Resonance Spectroscopy Analysis of Room Temperature Alcohol 2_Amino-2_(Hydroxymethyl) 1,3_Propane 2-Amino-4- [4·(2'曱ethoxyethoxy)phenyl]-6-[(3_π 咬 曱 ) yl) amine thiol] 吼唆-3,5-February 耷 Step 1: 10 4-(2 -methoxyethoxy)benzaldehyde 15

CH,

〇,,H, Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 20, M6.5 g (1.2 mol) of 4-pyrimidine is dissolved in dmf, and 20 g (0.12 mol) is hampered. Potassium, I34.6 g (1.2 mol), third butyric potassium, and 170.2 g (1.8 mol) of 2-chloroethylsulfonyl linkage were added. The reaction mixture was stirred at 80 ° C for 16 hours. For the treatment, the reaction mixture was concentrated under reduced pressure. The residue was extracted in 1 liter of ethyl acetate and extracted with 0.5 liter of 1> aqueous sodium hydroxide solution. The ethyl acetate phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained after concentration is distilled in a high vacuum (in -23- This paper scale applies to the National Standard for 117 (CNS) A4 specification (2丨〇X297 public) 1333487 A7 B7 V. Description of invention (22) 0.45 mbar&gt;Focus = l〇〇 °C). This gave 184.2 g (85% of theory) of product. MS (ESIpos): m/z = 181 (M + H)+. 5 Ή-NMR (300MHz » CDC13) : δ = 3.5 (s, 3H); 3.8 (tr, 2H); 4.2 (tr, 2H); 7.0 (d, 2H); 7·8 (d, 1H); (s, 1H). Step 2: 2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-amine-accepting bite _3,5-dicarbonitrile 10

Η CN S,,, NH,

Charge 15 18 g (100 mmol) of 4_(2-methoxyethoxy)benzaldehyde, 1 g (2 mmol) of cyanothioacetamide in 100 ml of ethanol And 2 〇 2 g (200 mmol) of N-methylfoquinone was heated in reflux for 3 hours. After cooling, the precipitated crystals were filtered off by suction, washed with little ethanol and dried under reduced pressure. Thus, 12 g (3 % of theory) of 2 Å was produced, which contained 莫.5 molar equivalent of N-methylfoamidine. ]yis (ESIpos) : m/z = 327 (Μ + H)+. H-NMR (300 MHz 'DMSO-d6): δ = 2.8 (tr, 4H, N-methyl- or s-----------) 4.2) (tr, 2H); 7.1 (d, 2H); 7·4 (d, 2H):; 7.6 (s, wide-area, 2Η) β -24- This paper scale applies to Chinese national standards (CNS) )A4 specification (210x297 mm) Line Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1333487 A7 B7 V. Invention Description (23) Step 3: 2-Amino-4-[4-(2-methoxyethoxy) Phenyl]_6-[(3-pyridylmethyl)amine sulfo]pyridine-3,5-dicarbonitrile

The Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs will print 4.28 grams (11.36 millimoles; starting material containing 〇.5 molar equivalents of N-methylfoquinone; therefore, purity is 86.6%) 2_amino group· 4·[4·(2·methoxyethoxy)phenyl]-6-amine sulfopyridine·3,5·dicarbonitrile is dissolved in 4〇15 L of DMF and then pa3.34 g (39.75 mmol) The ear) sodium bicarbonate and 2.48 g (15.1 mmol) of 3-pyridylmethyl gas hydrogenation were added. The suspension was stirred at room temperature overnight, 40 ml of ethanol was added and then the mixture was heated to about 40 C. Then 19 ml of water was added dropwise. The precipitate was filtered by suction and dried under reduced pressure. Thus, 3 7 g (78% of the theoretical value) product "MS (ESIpos): m/z = 418 (Μ + Η)+. H-NMR (300MHz, DMSO-d6): δ = 3.3 (s, 3H); 3.7 (ti·, 2H); 4.2 (tr, 2H), 4.5 (s, 2H), 7.1 (d, 2H); 7.35 (dd, 1H); 7.45 (d, 2H), 7.9 (d tr,1H), 8.1 (s, wide-area '2H); 8.45 (dd, 1H); 8 75 (d, -25- paper The scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1333487 A7 B7 V. Description of invention (24) 1H) 〇 Example 2 2-Amino-6-[(2-Ga-U-嗔. Sit-4 -yl)decylamine sulfo]-[4_(2-methoxyethoxy)phenyl]pyridine-3,5-dicarbonitrile

10 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printed 100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy) phenyl]-6-amine contiguous ratio Bite -3,5-one is dissolved in 1 ml of j) MF. After 15 minutes, 103 mg (1.23 mmol) of sodium bicarbonate and 77 2 mg (〇 46亳 mol) 4_chloroindolyl 2_milk-I, 3-cinc were added. The suspension was allowed to stand overnight at room temperature and water was added. The precipitate was dried by suction, washed with ethanol and diethyl ether and dried at 40 ° C under reduced pressure. This gave 123 mg (88% of theory) of product. 20 MS (ESIpos): m/z = 458 (Μ + H)+. H-NMR (300MHz, DMS0-d6): δ = 3·3 (s, 3H). 3 7 4.2 (tr, 2H); 4.5 (s, 2H); 7.1 (d, 2H); 7.45 (d 2ϊ) -Γ\^v 9 zti); 7.8 (s, 1H); 8.05 (s, wide area, 2H). Example 3 -26- 1333487 A7 B7 V. Description of the Invention (25) 2-Amino-4-[4-(2-decyloxyethoxy)phenyl]_6·[(2phenyl_13-thiazole_ 4_yl)methylamine sulfo]pyridine-3,5-dicarbonitrile

Dissolving 100 mg (0.31 mmol) of 2-amino- 4-[4-(2-decyloxyethoxy)phenyl]-6-amine contigyl-pyridyl-3,5-dicarbonitrile in 1 ml of DMF. Then, 103 mg (1.23 mmol) of sodium hydrogencarbonate and 96 4 mg (0.46 mmol) of 4-chloromethyl-2-phenyl-1,3-thiazole were added. The suspension was shaken at room temperature overnight and water was added. The temple was filtered by air suction, washed with ethanol and diethyl ether and dried under reduced pressure at 40 °C. This gave 149 mg (97% of theory) of product. MS (ESIpos): m/z = 500 (Μ + H)+. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Consumers' Cooperatives! H-NMR (300MHz &gt; DMS0-d6) : δ = 3.3 (s, 3H); 3.7 (tr, 2H); 20 4.2 (tr, 2H); 4.5 (s , 2H); 7.1 (d, 2H); 7.5 (m, 5H); 7.8 (s, 1H); 7.9 (m, 2H); 8.05 (s, wide-area, 2H). Example 4 2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-(thiophen-2-yl)-l,3-thiazol-4-yl) Methylamine sulfo]pyridine-3,5-dicarbonitrile-27- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1333487 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Description of the invention (26) 俨3

Dissolving 100 mg (0.31 mmol) of 2-amino-4-[4-(2-decyloxyethoxy) 10 phenyl]-6-amine sulfo-pyridine-3,5-dicarbonitrile in 1 ml of DMF. Then, 103 mg (1.23 mmol) of sodium hydrogencarbonate and 96.4 mg (0.46 mmol) of 4-oxomethyl-2-(thiophen-2-yl)-1,3-thiazole were added. The suspension was shaken overnight at room temperature and water was added. The precipitate was filtered off by suction, washed with ethanol and diethyl ether and dried at 40 ° C under reduced pressure. This gave 146 15 mg (84% of theory) product. MS (ESIpos): m/z = 506 (M + H)+. *H-NMR (300MHz » DMS0-d6) : δ = 3.3 (s, 3H); 3.7 (tr, 2H); 4.2 (tr, 2H); 4.6 (s, 2H); 7.15 (m, 3H); (d, 2H); 7.65 (d, 1H); 7.75 (d, 1H); 7·8 (s, 1H); 8-1 (s, wide, 2H). 20 Example 5 2-Amino-4-[4-(2-methoxyethyl lactyl)phenyl]-6-[(2-嗔-phen-3-yl)-1,3_ 嗔0 -4- Base] methylamine cross-link] π ratio bite-3,5-two month blue -28- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)

俨3

1333487 A7 B7 V. INSTRUCTIONS (27) 〒h3 will · mg_€mole)2. Amino- ortho-methoxyethoxy) 1 phenyl phenyl]_6·amine sulfo-Wei-3,5_ The dinitrile is dissolved in milliliters of dmf. Then 1 〇 3 mg (1.23 mmol) of sodium bicarbonate and 9 M mg (〇46 mA' Mo) 4 _ chloromethyl 2 - (嗟 -3- -3- yl)-1 3- 唉 λ U4· - ;, azole added. The suspension was shaken overnight at room temperature and water was added. The precipitate was transferred from the air-suction method and washed with ethanol and diethylbenzene and dried at 4 rc under reduced pressure. Thus obtained 15 141 mg (82% of theory) of product. MS (ESIpos): m/z = 506 (Μ + Η)+ 〇^-NMR (300MHz » DMSO-d6) : δ = 3.3 (s, 3H); 3.7 (tr, 2H); 4.2 (tr, 2H); 4.6 (s, 2H); 7.15 (d, 2H); 7.5 (d, 2H); 7.55 (d,. 1H); 7.7 (dd, 1H); 7.8 (s, 1H); 8.1 (s, wide-area, 2H); 8.15 (d, 20 1H). Example 6 2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazole-4-yl; j-methyl}amine sulfo)-4-[4- (2-Hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile pathway 1 -29- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm)

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1333487 A7 B7 V. Description of Invention (μ) Step 1: 2-Amino-4-[4-(2-hydroxyethoxy)phenyl]_6-amine sulfopyridine -3,5-dicarbonitrile

The Ministry of Economic Affairs’ Intellectual Property Office employee consumption cooperative printed the first 12.46 g (75 mmol) of 4-(2-hydroxyethoxy) cumin, 15·2 g (15 〇 mmol) of cyanothio Acetamide and 1S 1S grams (15 Torr) were added to 75 ml of ethanol and heated under reflux for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure. The residue was dissolved in 1 aqueous sodium hydroxide solution and washed twice with ethyl acetate. The 15 sodium hydroxide aqueous phase was at 45. (: Acidification with 1 Torr of hydrochloric acid and filtration of the precipitated crystals by suction and dried under reduced pressure at 45 ° C. Thus obtained 12.05 g (51% of theory) product. MS (ESIpos): m/z = 313 (M + H)+, 330(M+NH4)+. !H-NMR (300MHz » DMS0-d6) : δ = 3.7 (t, 2H); 4.1 (t, 2H); 20 7.1 (d, 2H); 7.4 (d, 2H); 8.0 (br s, 2H). Step 2: 2-Amino-6·({[2-(4-phenylphenyl)-1,3-thiazole- 4-yl]methyl}amine sulfo)_4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile-30- This paper scale applies to China National Standard (CNS) A4 Specifications (210 X 297 mm) 1333487 Α7 Β7 V. Description of invention (29)

H2N, N 'SH

10 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative printed 6.91 g (22.12 mmol) of 2-amino-4-methyl 4-[4-(2-hydroxyethoxy)phenyl]-6-amine sulfo-oxime唆-3,5-dinitrile is dissolved in! 50 ml of DMF. Then 7'44 g (66.35 mmol) of 1,8-diazabicyclo[5 4.〇]*j--7-ene and 10.8 g (44.24 mmol) of 4-chloromethyl group 2-(4·Phenylthiazole was added. The suspension was stirred at room temperature overnight, 5 g of saponin was added and the mixture was concentrated under reduced pressure. The mixture was applied to the slabs by chromatography. Purification (mobile phase: toluene to toluene / ethyl acetate hydrazine: hydrazine mixture) β thus obtained 5.5 g (47% of theory) product. MS (ESI pos): m/z = 521 (Μ + Η) + iH-NMR (300ΜΗζ, DMS0-d6) : δ = 3.7 (dt, 2H); 4.1 (t, 2H); 4.6 (s5 2H); 4.9 (t, 1H); 7.1 (d, 2H); 7.4 (d, 2H) ; 7.5 (d, 2H); 20 7.9 (m, 3H); 8.1 (br s, 2H) » Route 2: or 'may not separate 2-amino-4-[4-(2-carbylethoxy) Phenyl]- 6-amine contigyl-3,5-pyridinium dinitrile by 2-[4-(2-fylideneethoxy)- phenylidene]propanol Thioacetamide and 4-methylmethyl·2_(4_gasphenyl)_ -31- This paper scale applies to Yin Guo National Standard (CNS) A4 specification (210x297 mm) 1333487 Α7 Β7 V. Invention Description (30) 1,3-thiazole is reacted to prepare a product: step 1 :

2-[4-(2-hydroxyethoxy)-benzylidene]malononitrile 5 j〇H-+Ν^Λ — Ν 10 1000 g (5.85 mol) 4-(2-hydroxyethoxyl) Benzo-benzaldehyde and 425 g (6.43 mol) of malononitrile were dissolved in 5000 ml of isopropanol and 5 g (0.059 mol) of hexahydropyridine was added. The mixture was heated to 80 ° C for 16 hours and then cooled to 3 ° C to separate the product. The product was filtered off 15 and washed with 400 mL of ice cold isopropanol. It was then dried in a vacuum (40 mbar) at 50 ° C for 45 hours. Yield: 1206 g (94.6% of theory), slightly yellow crystals ^-NMR (400 MHz &gt; CDC13): 3.95-4.32 m (4 Η), 6.95 - 7.15 Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative ΟΗ

CN

(m, 2H), 7.61 (s, 1H), 7.85 - 7.95 (m, 1H). 20 Step 2: 4-Chloromethyl-2-(4-murine phenyl)-1,3-嗟α sit-32- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1333487 A7 B7 V. Description of the invention (31)

Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, 171:65 g (1.0 mol) of 4-chlorothiobenzene f-amine in 550 ml of isopropanol and during the 3 hour period at a maximum temperature of 30 ° C. 133.3 g of 10 (1.05 mol) 1,3-dichloroacetone was added. The mixture was then stirred at 40 ° C for 5.5 hours and at 20 ° C for 10 hours. The mixture was then heated to 55 ° C for 7.5 hours to complete the reaction. The product was separated by cooling to 10 ° C and 950 ml of water was added. The pH was adjusted to 4 to 5 with sodium hydroxide solution and the product was filtered off by suction. 15 Yield: 220.9 g (91% of theory) white to slightly yellow crystals! H (400MHz » CDC13): 4.90 (s, 2H, CH2), 7.5 - 7.55 (m, 2H), 7.85 (s, 1H, thiazole ), 7.9 - 7.95 (m, 2H). Step 3: 2-Amino-6-({[2-(4-phenylphenyl)-1,3-n.sup.4-yl)methyl}amine contig)-4-[4_20 ( 2-Hydroxyethoxy)phenyl]-3,5-pyridinedicarbonitrile-33- This paper scale is applicable to China National Standard (CNS) A4 specification (2丨Ox297 mm) 1333487 Α7 Β7 V. Invention description (32)

H2N

10 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 428.4 g (2_0 mol) 2-[4-(2-hydroxyethoxy)_stupidylmethyl] propene January, 108.4 g (1·〇 5 mol) 2 · cyanothioacetamide and 244 g (1.0 mol) 4-gas methyl-2-(4-phenylphenyl)_ι, 3-thiazole suspended in 34 liters of methanol and 556.1 grams (3.0 moles) of tributylamine was added over a 6 minute period. The mixture was then stirred at room temperature for 20 hours and the product was filtered. After drying in vacuo, the crude product (360.8 g, crude yield: 70% of theory) was suspended in 3 liters of dioxane at 35. Stir for 2 hours. The product was filtered off and dried in vacuo. The white crystals were then recrystallized from tetrahydrofuran/water (1:1) and purified. Yield: 353.5 g (68% of theory) of white crystals MS (El): m/z = 520.00 Example 7 2 〇 2-amino-4-[4-(2-methoxyethoxy)phenyl] -6-[(2-Acridinemethyl)amine contig]pyridin-3,5·dicarbonitrile•34- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 1333487 A7 B7 V. Description of invention (33)

〒h3 / Φ 5 νο\Α^ον

Η2Ν^^Ν八SH 100 mg (0.31 mmol) of 2-amino-4-[4-(2-decyloxyethoxy) 10 phenyl]-6-amine sulfo-pyridine-3, The 5-dinitrile was dissolved in 1 ml of DMF. Then, 103 mg (1.23 mmol) of sodium hydrogencarbonate and 75.4 mg (0.46 mmol) of 2-pyridylmethyl chloride hydrogenate were added. The suspension was stirred at room temperature overnight and water was added. The precipitate was filtered off by suction, washed with ethanol and diethyl ether and dried under reduced pressure at 40 °. This gave 104 mg (81% of the theoretical value) product. MS (ESIpos) : m/z = 418 (Μ + Η)+ Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives] H-NMR (300ΜΗζ, DMS0-d6) : δ = 3.3 (s,3H); 3.7 (tr , 2H); 4.2 (tr, 2H); 4.6 (s, 2H); 7.1 (d, 2H); 7.4 (dd, 1H); 7.45 (d,. 2H); 7.65 (d, 1H); 7.75 (tr , 1H); 8.0 (s, wide area, 2H); 8.5 (d, 20 1H). Example 8 2-Amino-4-[4-(2-decyloxyethoxy)phenyl]-6-[(2-methyl-1,3-thiazol-4-yl)indolyl]sulfonate Pyridyl-3,5-dicarbonitrile-35- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1333487 Α7 Β7 V. Invention description (34) ?H3

9Η3

Dissolving 100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy) 10 phenyl]-6-amine sulfo-pyridine-3,5-dicarbonitrile in 1 ml of DMF. Then, 103 mg (1.23 mmol) of sodium hydrogencarbonate and 90.5 mg (0.61 mmol) of 4-methylmethyl-2-mercapto-1,3-thiazole were added. The suspension was stirred at room temperature overnight and water was added. The precipitate was filtered by suction and dried under reduced pressure at 40 °C. This gave 88.8 mg (66.2% of theory) of 15 products. MS (ESIpos): m/z = 438 (Μ + Η) + Example 9 2-amino-4-[4-(2-decyloxyethyl)phenyl]-6-[(2-amino) -1,3-嗟sa-4_yl)decylamine sulfo]pyridine-3,5-dicarbonitrile 20 -36- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1333487 A7 B7 V. Invention description (35)

?h3 5 jT + Cl 100 mg (0.31 mmol) of 2-amino-4-[4-(2-decyloxyethoxy)phenyl]-6-amine sulfo-pyridine-3,5 - The dinitrile was dissolved in 1 ml of DMF. After 10, 103 mg (1.23 mmol) of sodium hydrogencarbonate and 68.3 mg (0.46 mmol) of 4-cyclodecyl-2-amino-1,3-thiazole were added. The suspension was stirred at room temperature overnight and water was added. The precipitate was filtered off by suction, washed with ethanol and diethyl ether and dried under reduced pressure at 40 °. This gave 115.9 mg (86.2% of theory) product. 15 MS (ESIpos): m/z = 439 (M + H)+. Example 10 2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-[(2-(2-° ratio))-1,3· 嗔π坐-4 - base) thiol] amine base] π than bite-3,5-dila.

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1333487 A7 B7 V. Description of invention (36) 50 mg (0.15 mmol) 2-amino group 4-4-[4-(2 -Methoxyethoxyxyl) Styrene]-6-amine contig-bite-3,5-two rides are dissolved in 1 ml. Then, 51.5 mg (0.61 house mole) of sodium hydrogencarbonate and 58.6 mg (0 23 mmol) of 4-methylmethyl-2-(2-pyridyl)-1,3-thiazole were added. The suspension was stirred at room temperature overnight and water was added. The precipitate was filtered off by suction, washed with ethanol and diethyl ether and dried at 40 ° C under reduced pressure. This gave 67 4 mg (87.9% of theory) of product. MS (ESIpos): m/z = 501 (M + H)+. Example 11 10 2-Amino-4-[4-(2-hydroxyethoxy)phenyl]·6_{[(2-methyl-i,3-thiazole-4-yl)indolyl]-amine cross-base} Beta ratio bite-3,5-dicarbonitrile 15

Ν' ch3 into c

Cl : HCI meter Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 .0Η 0〆

Dissolve 31.2 mg (0.1 mmol of m-amino-4-(4-(2-hydroxyethoxy))]-6-amine sulfo-pyridine-3,5-dicarbonitrile in 〇·3 ml of DMF Then 33.6 mg (〇.4 mmol) sodium bicarbonate and 26 7 mg (〇15 mmol) 4-mercapto-2-a-1,3-thiazole hydrochloride were added. Room Temperature Line 38- 1333487 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Β7 Β7 V. Description of Invention (37) Stir overnight, filter and purify by preparative HPLC [column: Macherey-Nagel VP 50/21 Nucleosil 100 -5 Cl8 Nautilus, 20 x 50 mm; flow rate: 25 ml/min; gradient (A = acetonitrile, B = water + 0.3% trifluoroacetic acid): 0 min 10% A; 2.0 min 10% A; 6.0 min 5 90% A; 7.0 minutes 90% A; 7.1 minutes 10% A; 8·0 minutes 10% A; detection: 220 nm]. The appropriate fraction was concentrated to give 20.2 mg (47.7% of theory) of product. MS (ESIpos): m/z = 424 (Μ + Η) + ° Example 12 10 2-Amino-6-{[(2-amino-1,3-indolyl)-yl)-yl]amine-retentyl}- 4-[4-(2-fluorenylethoxy)phenyl]-p-pyridine-3,5-dicarbonitrile 15 Η, Ν

20 Dissolve 31.2 mg (0.1 mmol) of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-amine sulfo-pyridine-3,5-dicarbonitrile in 0.3 ml In DMF. Then 33.6 mg (0.4 mmol) of sodium bicarbonate and 22.3 mg (0-15 mmol) of 4-amino-2- gas-1,3-thiazole were added. Stir the suspension at room temperature -39- This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

, ΟΗ Ο

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1333487 A7 B7 V. Description of the invention (3 days and nights, filtered and purified by preparative HPLC • [column: ^^(;1^1·^-Nagel VP 50/ 21 Nucleosil 100-5 Cl8 Nautilus, 20 χ 50 mm ; Flow rate: 25 ml/min; Gradient (A = acetonitrile, B = water + 0.3% trisacetic acid): 0 min 10% A; 2.0 min 10% A; 6.0 min 90% A; 5 7.0 minutes 90% A; 7.1 minutes 10% A; 8.0 minutes 10% A; detection: 220 nm]. The appropriate fraction was concentrated to give 35.7 mg (84.1% of theory) of product. MS (ESIpos) : m/z = 425 (Μ + Η) + Example 13 10 2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-({[2-(4-?咁-)-1,3-嗟嗤-4-yl]methyl}amine contig) π ratio bite-3,5-February step 1: 4-[4-(gas thiol)-1,3 -thiazol-2-yl]morphine

11.51 g (78.76 mmol) of 4-fosfos carbodiimide and 10.00 g (78.76 mmol) of dioxane in 100 ml of ethanol were heated in reflux 20 for 1 hour. After cooling, the colorless solid precipitated from the pink solution was filtered by suction and washed twice with ethanol. This gave 12.96 g (75% of theory) of product. MS (ESIpos) · m/z = 219 (Μ + Η)+ Step 2 : -40- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm)

1333487 A7 B7 V. INSTRUCTIONS (39) 2-Amino-4·[4-(2-methoxyethenyl)phenyl]-6-( {[2-(4-)) 1,3-thiazol-4-yl]methyl}amine sulfo)pyridine-3,5-dicarbonitrile

N SH CJ^〇 CH,

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative 10, 2 g (6·13 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-amine sulfonate Pyridine-3,5-dicarbonitrile and 2.68 g (12.26 mmoles of M-(4-chloromethyl)-1,3-thiazol-2-yl]-isfosate were dissolved in anhydrous DMF (50 mL) And 1.83 ml (12.26 mmol) of DBU was added. After stirring at room temperature for 15 hours, the solvent was removed with a rotary evaporator and the residue was purified by preparative HPLC [column: Kromasil 100 C18 250x20mm, ΙΟμπι; acetonitrile/water gradient: 10% acetonitrile in 3 minutes; then increased to 80% acetonitrile over a period of 30 minutes; flow rate: 25 ml/min. clock]. This gives 1.70 g (55% of theory) of product 20 MS (ESIpos): m/z = 509 (Μ + Η) + 'H-NMR (300 ΜΗζ &gt; DMSO-d6) : δ = 3.3 (m, 7H); 3.7 (m, 6H); 4.2 (tr , 2H); 4.4 (s, 2H); 6.95 (s, 1H); 7.15 (d, 2H); 7.45 (d, 2H); 8.0 (s, wide-area, 2H). The examples listed in Table 3 are similar. Prepared in Example 13. This is used as a -41 paper scale for the Chinese National Standard (CNS) A4 specification (210x297 mm) 1333487 Ministry of Economic Affairs wisdom Produced by the Bureau of Staff and Consumers Cooperatives A7 B7 V. Description of the invention (4〇) The starting material of chloromercaptothiazole is either commercially available or can be prepared analogously to Example 13 Step 1

-42- The paper size is applicable to China National Standard (CNS) A4 specification (2丨0 X 297 mm) 1333487 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 B7 V. Invention description (4!)

-43- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 1333487 A7 B7 V. Description of invention (42) Example No. 18 Structural formula Expected molecular weight 487

[M +Η]Τ Measured value 488 H0,

S

Loading

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1333487 A7 B7 V. Invention description (43) Example No. 20 Structure

III 534 [Μ+ΗΓ measured value 535 CH, I 3 0, 21

α Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-4 The paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 1333487 A7 B7 V. Description of invention (44) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-46- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1333487 A7 B7 V. Description of invention (45) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

25 59

This paper scale applies to China National Standard (CNS) A4 specification (210x297 public Chu) 1333487 A7 B7 V. Invention Description (46) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-48- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

1333487 A8 Patent Application No. 91135620 B8 ROC Patent Appln. No. 91135620 C8 Correction of the Chinese patent application without a scribe line Replacement - Annex (II) D8 Amended Claims in Chinese - EncUll) VI. Patent Application Scope (Republic of China 99 Submitted on August 6th) (Submitted on August 6. 2010) 1. A compound of formula (I), or a salt thereof (I), where ίο Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative prints 15 2. 20 represents the number 2, 3 or 4, represents hydrogen or (CrC4)-alkyl, and represents pyridyl or thiazolyl, part of which can be Substituted by: (CrQ)-alkyl, halogen, amine, dimethylamino, ethyl hydrazino, fluorenyl, pyridylamino, thienyl, furyl, imi. Sitting base, α than bite base, 福福 林 基 ,, thio 福 ° ° Lin, hexahydro 0 ratio. Fixed base 'six nitrogen σ ratio π well base, N-(Ci-C4)-calcyl hexanitrogen ratio σ well base, β ratio σ each bite base, σ number spyryl group, different 4 ° sitting base, 0f bite base, σ is a phenyl group substituted by any of the (crc4)-alkyl-substituted thiazolyl groups or any of the phenyl groups substituted by a halogen, (crc4)-alkyl or (crc4)-alkoxy group up to three times. For example, the compound of formula (1) in the scope of patent application, or its salt, wherein, represents the number 2, η RR η. The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91500B-connected 2 1333487 A8 B8 C8 _D8_ VI. Patent application range R1 stands for hydrogen, fluorenyl or ethyl, and R2 stands for pyridyl or thiazolyl, which can be partially substituted by: methyl, ethyl, fluoro, ethane, amine, Dimercaptoamino group, etidylamino group yl group '2-atb octamidyl ' 4- 咐 胺 amine ' 5 11 thiophene, 0 to bite base, ruthen 11 base, hexahydro B is a phenyl group, any thiazolyl group substituted by a fluorenyl group or any phenyl group substituted by a chlorine or a decyloxy group up to three times. 3. The compound of the formula (I), or a salt thereof, according to the first aspect of the patent application, wherein 10 η represents the number 2, R1 represents hydrogen or a fluorenyl group, and R2 represents a pyridyl group or a thiazolyl group, and a part thereof may be as follows Substituted: fluorenyl, chloro, amino, dimethylamino, ethyl hydrazino, sulfhydryl, 2-吼 σ sylamino, 4-° ratio dimethylamino, porphinyl, σ ratio Pyridyl, fenofyl, 2-methylthiazole-5-yl, phenyl, 4-phenylphenyl or 3,4,5-trimethoxyphenyl. 4. If the compound with the following structural formula in the scope of patent application No. 1 to 3 is printed, the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs prints 20 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1,333487 A8 B8 C8 D8 VI. Patent application scope or its salts. A method for preparing a compound of the formula (I) according to the first aspect of the patent application, which is characterized in that the compound of the formula (II) m, wherein η and R1 are defined as the reaction between the compound of formula (III) and the compound of formula (III), r2-ch, -x (III) printed by the Intellectual Property Office of the Ministry of Economic Affairs, employee consumption cooperative, R2 definition as application In the first item of the patent scope, and X represents a release 15 ionization. A compound of the formula (I) in claim 1 of the patent application for use in the prevention and/or treatment of a disease associated with the adenosine A1 receptor. A pharmaceutical product comprising at least one compound of the formula (I) as in the first aspect of the patent application and at least one adjuvant. 20 8. A pharmaceutical product comprising at least one such as the scope of the patent application. 1. 6. 7. The paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 1333487 as B8 C8 _D8_ 6. Patent application A compound of formula (i) and at least one other active compound. 9. Use of a compound of formula (I) according to claim 1 in the preparation of a medicament for the prevention and/or treatment of diseases of the cardiovascular system. 10. Use of a compound of the formula (I) in the first aspect of the patent application for the preparation of a medicament for the prevention and/or treatment of inflammatory and neurogenic inflammatory diseases, neurodegenerative diseases and pain. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. This paper scale applies the Chinese National Standard (CNS) A4 specification (210x297 mm).